Pneumonic disease and otitis media, especially in children up to the age of about 12 years, represent a serious global health problem which is aggravated by the ever-growing ability of bacteria to mutate into forms that are increasingly resistant to the therapeutic effect of the various antibiotics which are the most effective medications against them. In the United States alone, approximately 4.3 million cases of pneumonia occur in persons of all ages annually and about half of them are caused by bacteria. About 2.5 million visits to physicians are made in the U.S. for the purpose of seeking treatments for otitis media—again about 50% attributable to bacteria. Otitis media is known to be largely a disease of young children.
It has been estimated that about 4 million children throughout the world die annually from acute respiratory diseases, preponderantly in developing countries. Studies show that Streptococcus pneumoniae is the leading cause of bacterial pneumonia in developing countries and a major cause of child mortality.
All of these problems have been complicated by the fact that accurate diagnosis of bacterially caused respiratory infection, and acute ear infection (i.e., otitis media) in children was slow and difficult until recently. It has been known for some years that bacterial antigens were present in bodily fluids of persons infected with pneumococcal pneumonia, such as e.g., blood, sputum, urine, etc., but until recently there was little progress in using this knowledge as the basis for developing a reliable test for such antigens. In the meantime, the standard for accurate diagnosis of pneumococcal pneumonia and other Streptococcus pneumoniae—caused diseases has been a bacterial culture test which usually required some days to complete and had other considerable drawbacks, such e.g., as the difficulty of obtaining a suitable sample for culturing and the drawback of having to medicate the patient while awaiting the culture test outcome with a broad spectrum antibiotic, all of which drawbacks are well documented in the medical literature.
In 1999, the United States Food and Drug Administration approved a rapid (i.e. about 20 minutes) immunochromatographic (“ICT”) bioassay for the detection of Streptococcus pneumoniae in bodily fluids, particularly urine. This test, which is commercially available from Applicants' assignee under the trademark NOW®, detects the C-polysaccharide antigen which is present in all serotypes of Streptococcus pneumoniae. In adults and most teenagers, the test has a sensitivity of 78% for pneumococcal pneumonia infections and 82-86% for bacteremic forms thereof and a specificity of over 95%. See Dominguez, J., Gali, N. Blanco, S. et al, Detection of Streptococcus pneumoniae antigen by a rapid immunochromatographic assay in urine, Chest 2001, vol. 119, 243-9; Yu V. L., Kellog, J. A, Plouffe, J. F. et al, Evaluation of the Binax Urinary, Gram stain and sputum culture for Streptococcus pneumoniae in patients with community-acquired pneumonia, 38th Annual Meeting of the Infectious Disease Society of America, New Orleans, La., Abstract #262 (2001).
The NOW® bioassay is described and claimed in co-pending, commonly assigned U.S. patent application Ser. No. 09/399,710 filed Sep. 16, 1999, and also its parent application Ser. No. 09/156,486 filed Sep. 18, 1998 and now abandoned.
A study of pneumonia conducted in China found that children with nasopharyngeal carriage of Streptococcus pneumoniae had high rates of positive urine results in the NOW® test even when they had no pneumonic disease and that the test results accordingly did not fit the sensitivity and specificity profile established with adult subjects. A study in Gambia found that 87% of well children tested were nasopharyngeal carriers of Streptococcus pneumoniae and that 55% of these, or about 47% of this population, gave false positive results in the Binax NOW® test. See Adegbola, R. A., Obaro, S. K., Biney, E. and Greenwood, B. M., Evaluation of Binax NOW® Streptococcus pneumoniae urinary antigen test in children in a community with a high carriage rate of pneumococcus, Pediatr. Infect. Dis. J. 2001, July; 20 (7) 718-719. See also Dowell, S. F., Garman, R. L., Liu, G., Levine, O. S. and Yang, Y. H., Evaluation of Binax NOW® as assay for the detection of pneumococcal antigen in urine samples performed among pediatric patients, Clin Infect Dis. J. 2001, vol. 32, 824-825 (2001). A similar study conducted among 210 children in Quito, Ecuador, confirmed that urine from children with nasopharyngeal carriage of Streptococcus pneumoniae gives a high proportion of false positive results in the Binax NOW® test. See Hamer, D., Egas. J., Estrella, B., MacLeod MacLood, W. et al, 2002. An assessment of the Binax NOW® Streptococcus Pneumoniae urinary test in children with Nasopharyngeal pneumococcal colonization, (Publication in press).
An article reviewing published studies performed on Scandinavian and Israeli children confirms that young children in these areas have a high rate of nasopharyngeal colonization, not only of Streptococcus pnuemoniae but also of the bacteria that are known to cause disease states that resemble pneumococcal pneumonia, including especially non-typable Haemophilus influenzae and Moraxella catarrhalis which, with Streptococcus pneumoniae, are the most common causes of otitis media. Among other agents that tend to colonize the nasopharynx and are causatives of both pneumonic illness clinically very similar to pneumococcal pneumonia and otitis media are Staphylococcus aureus, a number of other bacteria and some viruses. See Harper, M. B., Nasopharyngeal colonization with pathogens causing otitis media; how does this information help us? Pediatr Infec. Dis. J. vol. 18, 1120-1124 (1999).
Copending, commonly assigned U.S. application Ser. No. 09/518,165 filed Mar. 1, 2002, describes and claims rapid immunochromatographic tests for detecting bacterial carbohydrate antigens in human bodily fluids, including urine.
The methodology for lessening and/or eliminating false positives in child carriers who are colonized nasopharyngeally as described herein is applicable to the modification of tests for antigens of other bacteria which tests are disclosed in copending, commonly assigned application Ser. No. 09/518,165 as well as to the test for Streptococcus pneumoniae antigens described in commonly assigned application Ser. No. 09/397,110, now U.S. Pat. No. 6,824,997.
In general, the development of rapid, reliable, specific and sensitive assays for antigens of bacteria causative of common respiratory tract and ear infections in children—and especially pneumonia and otitis media because of their high incidence—is important to complement the strategies that the Centers for Disease Control in the United States and the World Health Organization globally have formulated for decelerating the pace of development by causative bacteria of strains resistant to antibiotic therapy.